Pancreatic cancer is the fourth leading cause of cancer-related deaths among men or women in the U.S. It has the lowest 5-year survival (4%) of all cancers and has been difficult to study due to its rapidly fatal course and the lack of intermediate endpoints or early markers for the disease. Cigarette smoking is one of the few documented environmental risk factors. This study will use previously collected germ-line DNA and epidemiologic data from one of the largest population-based, case-control studies of pancreatic cancer to investigate associations between risk of adenocarcinoma of the pancreas and polymorphisms in candidate DNA repair, cell-cycle control, and oxidant defense genes. The main study was conducted in the San Francisco Bay Area between 1994 and 2001 and used random digit dialing and Health Care Finance Administration lists to identify controls. Genomic DNA and questionnaire information is available on 309 cases and 964 population-based controls. DNA repair pathways are known to be involved in correcting diverse forms of damage induced by agents such as tobacco smoke. Recent studies indicate that DNA repair pathways cross talk with pathways involved in cell cycle regulation such that cell-cycle delay or arrest allows for optimal DNA repair. DNA repair capacity is known to vary among individuals and is likely to be genetic. Genetic variation in carcinogen metabolism and DNA repair has been shown to play a role in susceptibilities to smoking-related cancers. We will analyze genomic DNA from cases and controls for known polymorphisms in genes involved in pathways for base excision repair, nucleotide excision repair, double-strand break repair, direct repair, cell-cycle control, and oxidant defense. We will estimate genotype and allele frequencies, examine main gene (genotype) effects, and explore potential genotypesmoking and genotype-genotype interactions as they relate to the risk of adenocarcinoma of the pancreas. We anticipate that these data will contribute to our understanding of disease mechanisms, and may ultimately improve the prevention, detection and treatment of pancreatic cancer.